WO2019241847A1 - Conjugué thérapeutique médicament-protéine de liaison à gpiib/iiia et son utilisation - Google Patents
Conjugué thérapeutique médicament-protéine de liaison à gpiib/iiia et son utilisation Download PDFInfo
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- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
Definitions
- the specification is in the field of platelet and cancer biology, haematology and medicine.
- the specification describes activated platelet binding proteins including antigen-binding fragments of antibodies and antibody drug conjugates (ADCs) comprising same including compositions and methods of using said binding proteins and ADCs.
- ADCs antibody drug conjugates
- Antibody drug conjugates represent an emerging class of therapeutics comprising an antibody conjugated to a drug such as a cytotoxic or immunomodulatory drug via a chemical linker.
- the therapeutic concept of ADCs is to combine binding capabilities of an antibody with a drug, where the antibody is used to deliver the drug to a tumor cell by means of binding to a target tumor cell antigen.
- the expression level of traditional tumor antigens within a tumor can be inadequate for effective tumor reduction and there is a need for new approaches to make ADC more effective. Even if the expression level is adequate, the ability of the ADC to access tumor cells in the solid tumor microenvironment about which little is understood, may lead to treatment failures. Nanoparticle based approaches have been used to try to trap ADC within solid tumors. SUMMARY OF THE DISCLOSURE
- composition includes a single composition, as well as two or more compositions; reference to “an agent” includes one agent, as well as two or more agents; reference to “the disclosure” includes single and multiple aspects of the disclosure and so forth.
- the present disclosure describes and enables a binding protein drug conjugate (also referred to as an ADC or immunoconjugate) for delivering a therapeutic drug to a tissue comprising activated platelets comprising (i) a binding protein comprising an antibody variable domain that binds specifically to the activated form of platelet-specific glycoprotein (GP)IIb/IIIa conjugated to (ii) a therapeutic drug, wherein the binding protein concentrates the therapeutic drug to a target tissue comprising activated platelets.
- a binding protein drug conjugate also referred to as an ADC or immunoconjugate
- the present disclosure describes and enables a binding protein drug conjugate for delivering a therapeutic drug to a tumor comprising (i) a binding protein comprising an antibody variable domain that binds specifically to the activated form of platelet- specific GPIIb/IIIa conjugated to (ii) a therapeutic drug, wherein the binding protein concentrates the therapeutic drug in the tumor microenvironment and provides targeted delivery of the therapeutic drug to the tumor cells.
- the therapeutic drug is chemotherapeutic prodrug and the binding protein drug conjugate comprises a cleavable linker and optionally a spacer between the prodrug and the binding protein which upon cleavage of the linker releases the active chemotherapeutic drug from the binding protein.
- the cleavable linker is a pH sensitive linker, such as a hydrazone or cis-aconityl, providing a non-specific pH sensing mechanism to provide activation or release of the therapeutic drug in a mildly acidic environment.
- a pH sensitive linker such as a hydrazone or cis-aconityl
- a disulfide linker is employed to release the therapeutic drug based upon the higher reducing potential found within the tumor microenvironment.
- hindrance groups can be introduced near the cleavage site.
- the cleavable linker is selectively cleaved by a molecule present in the tumor stroma.
- cleavable linker comprises a dipeptide, such as Val-Cit, Phe-Lys and Val-Ala.
- the binding protein is an Fv, scFv, di-scFv, diabody, triabody, tetrabody, Fab, F(ab')2, bispecific antibodies, full length antibody, chimeric, human etc antibody.
- Non-Ig binding proteins include monobodies, anticalins, and Darpins, LoopDarbins affibodies (Jost et al. Current opinion in Structural Biology 2014 27:102-112). Synthetic antibody mimetic s are also contemplated, as are ibodies (Adalta).
- the binding protein and/or the therapeutic drug are modified for conjugation (coupling). In one embodiment, the modifications are for site- specific conjugation. In one embodiment, the binding protein and the therapeutic agent are conjugated by sortase A mediated conjugation.
- the therapeutic drug is selected from the group consisting of a mitotic inhibitor, a plant alkaloid, and an anti-tumor antibiotic.
- the antibody variable domain binds an epitope of GPIIb/IIIa recognised by a scFv comprising of an amino acid sequence set forth in SEQ ID NO: 1 or 5.
- the antibody variable domain comprises a complementary determining region (CDR) of the heavy chain variable region (V H ) having the sequence of SEQ ID NO:2 or 6 and/or a CDR of the light chain variable region (V L ) having the amino acid sequence of SEQ ID NO: 3 or 7.
- CDR complementary determining region
- Variant sequences are also contemplated which have a small number of modified amino acids as known in the art while retaining or displaying enhanced binding and stability features.
- Reference to a small number includes for example 1 amino acid difference, or 2, 3, 4, 5, 6 amino acid substitutions, deletions such as conservative substitutions or use of unnatural amino acids.
- the antibody variable domain comprises a heavy chain variable region (VH) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 2 or 6.
- VH heavy chain variable region
- the antibody variable domain comprises a light chain variable region (VL) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 3 or 7.
- the antibody variable domain comprises a heavy chain variable region (V H ) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 2 or 6 and a light chain variable region (VL) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 3 or 7.
- the antibody variable domain comprises an amino acid sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 1 or 5.
- the antibody variable domain is derived from a human scFv library.
- Reference to a spacer includes a self immolative spacer, such as a para- aminobenzylalcohol (PABA) spacer or a non-self immolative spacer.
- a self immolative spacer such as a para- aminobenzylalcohol (PABA) spacer or a non-self immolative spacer.
- PABA para- aminobenzylalcohol
- the cytotoxic agent is cytotoxic to tumour cells at nanomolar concentrations, picomolar concentrations or less.
- the binding protein drug conjugate comprising a detectable label or molecule suitable for imaging tumors, diagnostic or monitoring.
- the ratio of antibody variable domain to drug is 1:1 or 1:2.
- the ratio of antibody variable domain to drug is 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.
- the binding protein drug conjugate as described herein is in the form of a composition including a pharmaceutical composition.
- Pharmaceutical compositions include pharmaceutically acceptable salts and isoforms.
- the composition comprises a pharmacologically or physiologically acceptable diluent and/or carrier.
- composition as described herein is for use in medical therapy or imaging.
- methods for imaging cancer are provide using the herein described binding proteins.
- composition comprising the binding protein drug conjugate as described herein in, or in the preparation of a medicament for, the treatment of cancer including reduction of solid tumors and reduced metastasis in a subject with cancer.
- the cancer is selected from the group consisting of breast cancer, lung cancer, a glioblastoma, prostate cancer, pancreatic cancer, colon cancer, colorectal cancer, head and neck cancer, mesothelioma, kidney cancer, ovarian, oesophageal, squamous cell carcinoma, triple negative breast cancer, and non-small cell lung cancer.
- a fusion protein or a kit is contemplated comprising a binding protein comprising the antibody variable domain as described herein labelled with a detectable label suitable for imaging, diagnostics, theranostics or monitoring.
- a fusion protein or a kit comprising a binding protein comprising the antibody variable domain as described herein conjugated via a suitable linker or spacer to a therapeutic agent suitable for therapy, theranostics or monitoring.
- the present disclosure provides a vector or host cell comprising a polynucleotide sequence capable of expressing the binding protein comprising the antibody variable domain as described herein.
- Illustrative polynucleotide sequences are provided in SEQ ID NOs 4 (encoding the SCE5 scFv- nucleotides 1 to 138 encode the vector leader sequence) and SEQ ID NO:8 (encoding the anti-LIBs scFv).
- the present disclosure provides a method of treating cancer and reducing metastasis comprising administering an effective amount of a binding protein drug conjugate as described herein to a subject with cancer.
- the present application provides a method for treating cancer in a subject, comprising (i) administering a binding protein comprising an antibody variable region that binds specifically to activated platelets such as to the activated form of platelet specific GPIIb/IIIa wherein the binding protein is coupled to an imaging contrast agent to determine the presence of activated platelets within a tumor (ii) administering a binding protein comprising an antibody variable region that binds specifically to activated platelets such as to the activated form of platelet specific GPIIb/IIIa wherein the binding protein is coupled to a drug such as a therapeutic or cytotoxic agent contingent upon a determination from (i) of the presence of activated platelets within a tumor.
- the binding protein comprises an imaging contrast agent and one or more anti-cancer drugs such as a therapeutic or cytotoxic agent.
- Therpeutic drugs include immune or inflammatory agonists.
- the binding protein drug conjugate is administered in combination with an additional drug selected from the group consisting of an anti- apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an alkylating agent, an anti-angiogenic agent, an anti-metabolite, a boron-containing agent, a chemoprotective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.
- the agent is attached or otherwise part of the ADC.
- a binding protein comprising an antibody variable domain that binds specifically to the activated form of platelet- specific GPIIb/IIIa in the preparation of a cancer imaging agent.
- FIG. 1 Structure of GGG-Val-Cit-PAB-MMAE and labeling strategy for the generation of scFv GpIIb/IIIa -Cy7-MMAE and Cathepsin B drug release.
- scFv GpiIb/IIIa was conjugated to GGG-Val-Cit-PAB-MMAE using an enzymatic sortase A reaction (I), followed by Cy7 conjugation, via NHS labelling to produce scFv GpiIb/IIIa - Cy7-MMAE (II).
- cathepsin B cleaves the scFv Gpnb/IIIa -Cy7-MMAE at the MMAE Val-Cit linker, releasing the potent MMAE for tumor killing (III).
- FIG. 1 scFv GpIIb/IIIa -Cy7-MMAE characterization and specific binding to activated platelets.
- A Coomassie (red) and near infrared (green) imaging of scFv GPiib/iiia - C y 7 - MMAE 0) > unmodified scFv GpiIb/IIIa (II), scFv mut -Cy7-MMAE (III) and unmodified scFv mut (IV). Yellow color indicates the overlap between Coomassie in red and near infrared in green.
- the scFv GPiib/iiia contains a V5 tag, which allows using an anti-V5-FITC secondary antibody for detection.
- FIG. 4 Tumor cells induce platelet activation.
- A, B Washed human platelets were added to MDA-MB-231 tumor cells and stained with a PE-conjugated anti-CD4l antibody (red) and an activation- specific anti-GPIIb/IIIa antibody (scFv GPiib/ ni a -GFP or FITC-conjugated PAC-l).
- Fluorescence imaging (20x) demonstrates that MDA-MB-231 cells induces platelet binding and activation as shown by scFv GPiib/ ni a -GFP and PAC-l binding (green)
- C Washed platelet rich plasma was added to MDA-MB-231, HT29, HT1080 and PC3 tumor cells and stained with a PE- conjugated anti-CD4l antibody and scFv GPiib/iiia or scFv mut , detected with an anti-V5- FITC antibody.
- Flow cytometry dot plots represent the gating strategy differentiating regions of cancer cells and platelets.
- the cancer cell region was further gated to select for CD4l-positive cancer cells (CD4l+ve).
- D Analysis of the CD4l-positive region demonstrated that 100% of platelets were activated upon incubation with cancer cells for 6 hours, determined by positive scFv GPiib/ ni a binding (red), which was equivalent to scFv GPiib/iiia binding to ADP-activated platelets (green).
- scFv GPiib/ ni a binding red
- scFv GPiib/iiia binding to ADP-activated platelets green
- Activated platelets are present in the tumor microenvironment and can be detected and imaged using the scFvGPiib/nia.
- A In vivo bioluminescence imaging of a representative mouse with an orthotopic mammary tumor.
- B In vivo bioluminescence imaging of metastatic lung and lymph node lesions, by shielding the area of the primary tumor.
- C In vivo fluorescence imaging of MDA-MB-231 tumor bearing mice injected with scFv GpIIb/IIIa -Cy7-MMAE.
- Activated platelets are present in the tumor microenvironment and can be detected and imaged using the scFvGPiib/iiia.
- A In vivo fluorescence imaging of MDA-MB-231 tumor-bearing mice, injected with scFv GPiib/iiia -Cy7-MMAE and scFv mut -Cy7-MMAE.
- B In vivo bioluminescence imaging of MDA-MB-231 tumor-bearing mice confirming primary tumor localization in the mammary gland.
- FIG. 7 Activated platelets are present in the tumor microenvironment but absent in the spleen and bone marrow.
- A, B Immunofluorescence imaging of tumor sections of MDA-MB-231 tumor-bearing mice injected with DyLight 649 anti- GPlbp (red) and scFv GPiib/iiia -GFP or scFv mut -GFP (green), counterstained with Hoechst® (blue).
- A Immunofluorescence imaging (20x) demonstrated the abundance of platelets within the tumor microenvironment (red), and the specificity of the platelet binding of scFv GPiib/iiia to tumor-associated platelets in vivo (green).
- C, D Flow cytometry of the spleen and bone marrow of BALB/C nude mice injected with PBS (control) or DyLight 649 anti-GPlbp and scFv GPiib/iiia -GFP or scFv mut -GFP.
- Black dotted lines represent guideline for normal range within the 95% interval published by Charles River for female BALB/C athymic nude mice. Data expressed as mean ⁇ SEM. WBC - white blood cells, ALT - alanine aminotransferase and ALP - alkaline phosphatase.
- FIG. 9 scFvGPiib/nia-MMAE binds to activated platelets and induces cancer cell killing.
- A Cytotoxicity assay of MDA-MB-231, HT29, HT1080 and PC3 tumor cells, cultured in GGG-Val-Cit PAB-MMAE and scFv GPiib/ ni a -MMAE, in the presence of cathepsin B (+C). Data expressed as mean ⁇ SEM.
- Figure 10 provides illustrative nucleotide and amino acids sequence of antibody variable domains and CDR and linker sequences of an anti-LIBs antibody clone.
- Figure 11 provides illustrative nucleotide and amino acids sequence of antibody variable domains and CDR and linker sequences of an SCE5 antibody clone described in the examples.
- SEQ ID NO: 4 Illustrative nucleotide sequence encoding amino acid sequence of single-chain (scFv) antibody against activated GPIIb/IIIa) (SCE5) including a leader sequence at nucleotides 1 to 138
- SEQ ID NO: 8 Illustrative nucleotide sequence encoding amino acid sequence of single-chain (scFv) antibody against activated GPIIb/IIIa) (anti- LIBs)
- antibody variable domains/regions, antigen binding fragments and parts thereof may be further clarified by the discussion in Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991.
- antigen binding site or domain of naturally occurring antibodies is formed by the precise juxtaposition of typically six hypervariable loops (also regarded as complementary determining regions or CDR) provided by the light chain variable region and the heavy chain variable region and aided by more conserved framework regions of the variable domains.
- antibody fragments or derivatives comprising an antibody variable region able to bind to the antigen include without limitation Fab, Fab', Fd, Fd', Fv, dAb, isolated CDR region, F(ab') 2 bivalent fragments, diabodies and liner antibodies.
- EU numbering system of Kabat will be understood to mean the numbering of an antibody heavy chain is according to the EU index as taught in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda.
- the EU index is based on the residue numbering of the human IgGl EU antibody.
- references herein to a range of, e.g., residues, will be understood to be inclusive.
- reference to "a region comprising amino acids 56 to 65 of SEQ ID NO: 1" will be understood to mean that the region comprises a sequence of amino acids as numbered 56, 57, 58, 59, 60, 61, 62, 63, 64 and 65 in SEQ ID NO: 1.
- Antibody variable domain refers to a binding protein that is capable of interacting with or specifically binding to an antigen (e.g., a platelet receptor or molecule, such as a protein, e.g., a glycoprotein).
- an antigen e.g., a platelet receptor or molecule, such as a protein, e.g., a glycoprotein.
- the antibody variable domain can be an antigen binding fragment of an antibody (e.g., a Fv or a scFv, etc.).
- Glycoprotein Ilb/IIIa Glycoprotein Ilb/IIIa (GPIIb/IIIa, also known as integrin al Ibp3 ) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids platelet activation.
- the GPIIb/IIIa complex is formed via calcium-dependent association of gpllb and gpllla, a required step in normal platelet aggregation and endothelial adherence.
- Platelet activation by ADP leads to the aforementioned conformational change in platelet gpIIb/IIIa receptors that induces binding to fibrinogen.
- GPIIb For the purposes of nomenclature only and not limitation an exemplary sequence of human GPIIb is set out in NCBI Gene ID: 3674, NCBI Reference Sequence: NG_00833l.l.For the purposes of nomenclature only and not limitation an exemplary sequence of human GPIIIa is set out in NCBI Gene ID: 3690, NCBI Reference Sequence: NG_008332.2. Additional sequences of GPIIb and/or Ilia from other species can be determined using sequences provided herein and/or in publically available databases and/or determined using standard techniques (e.g., as described in Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present) or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989)).
- the term "binds" in reference to the interaction of antibody variable domain or fusion protein comprising same with GPIIb/IIIa means that the interaction is dependent upon the presence of a particular structure (e.g., epitope) on the component.
- a particular structure e.g., epitope
- an antibody or antibody variable domain recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody binds to epitope "A”, the presence of a molecule containing epitope "A" (or free, unlabeled "A"), in a reaction containing labeled "A" and the protein, will reduce the amount of labeled "A" bound to the antibody or antibody variable domain.
- the term "specifically binds" shall be taken to mean that the binding interaction between the antibody variable domain and GPIIb/IIIa is dependent on the presence of the antigenic determinant or epitope.
- the binding region preferentially binds or recognizes a specific antigenic determinant or epitope even when present in a mixture of other molecules or organisms.
- the antibody variable domain reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with the specific component or cell expressing same than it does with alternative antigens or cells. It is also understood by reading this definition that, for example, a binding region the specifically binds to a particular component may or may not specifically bind to a second antigen.
- binding does not necessarily require exclusive binding or non-detectable binding of another antigen.
- the term “specifically binds” can be used interchangeably with “selectively binds” herein.
- reference herein to binding means specific binding, and each term shall be understood to provide explicit support for the other term. Methods for determining specific binding will be apparent to the skilled person. For example, a binding protein comprising the binding region of the disclosure is contacted with the component or a cell expressing same or a mutant form thereof or an alternative antigen. The binding to the component or mutant form or alternative antigen is then determined and a binding region that binds as set out above is considered to specifically bind to the component.
- epitope (syn. "antigenic determinant”) shall be understood to mean a region of GPIIb/IIIa to which a protein comprising a antibody variable domain of an antibody binds. This term is not necessarily limited to the specific residues or structure to which the protein makes contact. For example, this term includes the region spanning amino acids contacted by the protein and/or at least 5 to 10 or 2 to 5 or 1 to 3 amino acids outside of this region.
- the epitope is a linear series amino acids.
- An epitope may also comprise a series of discontinuous amino acids that are positioned close to one another when GPIIb/IIIa is folded, that is, a "conformational epitope".
- epitope is not limited to peptides or polypeptides.
- the term “epitope” includes chemically active surface groupings of molecules such as sugar side chains, phosphoryl side chains, or sulfonyl side chains, and, in certain examples, may have specific three dimensional structural characteristics, and/or specific charge characteristics.
- An epitope or peptide or polypeptide comprising same can be administered to an animal to generate antibodies against the epitope.
- a fusion protein comprising the antibody variable domain of the disclosure reduces or prevents binding of a recited antibody to GPIIb/IIIa, for example, a scFv consisting of a sequence set forth in SEQ ID NO: 1. This may be due to antibody variable domain binding to the same or an overlapping epitope as the scFv. It will be apparent from the foregoing that the protein need not completely inhibit binding of the antibody, rather it need only reduce binding by a statistically significant amount, for example, by at least about 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or 95%. Methods for determining competitive inhibition of binding are known in the art and/or described herein.
- the antibody is exposed to GPIIb/IIIa either in the presence or absence of the protein. If less antibody binds in the presence of the protein than in the absence of the protein, the protein is considered to competitively inhibit binding of the antibody.
- the competitive inhibition of binding is caused by the antigen binding domain of the protein on GPIIb/IIIa overlapping with the antigen binding domain of the antibody.
- the ability of antibody variable domains and ADC comprising same as described herein to bind to their cognate receptor on activated platelets in vivo in an appropriate subject or model is determined in accordance with the present invention and examples.
- “Overlapping" in the context of two epitopes means that two epitopes share a sufficient number of amino acid residues to permit a binding protein of the disclosure that binds to one epitope to competitively inhibit the binding of a recited antibody to GPIIb/IIIa that binds to the other epitope.
- the "overlapping" epitopes share at least 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 amino acids.
- recombinant shall be understood to mean the product of artificial genetic manipulation. Accordingly, in the context of an antibody or antigen binding fragment thereof, this term does not encompass an antibody naturally occurring within a subject’s body that is the product of natural recombination that occurs during B cell maturation. However, if such an antibody is isolated, in it is to be considered an isolated protein comprising an antibody variable region. Similarly, if nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein. A recombinant protein also encompasses a protein expressed by means of artificial genetic manipulation when it is within a cell.
- protein shall be taken to include a single polypeptide chain, i.e., a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains covalently or non-covalently linked to one another (i.e., a polypeptide complex).
- the series of polypeptide chains can be covalently linked using a suitable chemical or a disulfide bond.
- non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.
- polypeptide or "polypeptide chain” will be understood from the foregoing paragraph to mean a series of contiguous amino acids linked by peptide bonds.
- an "antibody” is generally considered to be a protein that comprises a variable region made up of a plurality of polypeptide chains, e.g., a polypeptide comprising a light chain variable region (VL) and a polypeptide comprising a heavy chain variable region (V H ).
- An antibody also generally comprises constant domains, some of which can be arranged into a constant region, which includes a constant fragment or fragment crystallizable (Fc), in the case of a heavy chain.
- a V H and a V L interact to form an Fv comprising an antigen binding region that is capable of specifically binding to one or a few closely related antigens.
- a light chain from mammals is either a k light chain or a l light chain and a heavy chain from mammals is a, d, e, g, or m.
- Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, dlgA and IgY), class (e.g., IgGi, IgG 2 , IgG 3 , IgG 4 , dlgAi and dIgA 2, IgAi and IgA 2 ) or subclass.
- antibody and antibody variable domain also encompasses humanized antibodies and humanized antibody variable domain, primatized antibodies and monized antibody variable domain, human antibodies and human antibody variable domains , synhumanized antibodies and chimeric antibodies and synhumanized and chimeric antibody variable domain.
- variable region refers to the portions of the light and/or heavy chains of an antibody as defined herein that specifically binds to an antigen and, for example, includes amino acid sequences of CDRs; i.e., CDR1, CDR2, and CDR3, and framework regions (FRs).
- the variable region comprises three or four FRs (e.g., FR1, FR2, FR3 and optionally FR4) together with three CDRs.
- V H refers to the variable region of the heavy chain.
- V L refers to the variable region of the light chain.
- CDRs complementarity determining regions
- CDR1, CDR2, and CDR3 refers to the amino acid residues of an antibody variable region the presence of which are major contributors to specific antigen binding.
- Each variable region typically has three CDR regions identified as CDR1, CDR2 and CDR3.
- the amino acid positions assigned to CDRs and FRs are defined according to Rabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (also referred to herein as "the Rabat numbering system”.
- V H FRS and CDRs are positioned as follows: residues 1-30 (FR1), 31-35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3) and 103- 113 (FR4).
- V L FRS and CDRs are positioned as follows: residues 1- 23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3) and 98-107 (FR4).
- "Framework regions" (hereinafter FR) are those variable domain residues other than the CDR residues.
- the term "Fv” shall be taken to mean any protein, whether comprised of multiple polypeptides or a single polypeptide, in which a V L and a V H associate and form a complex having an antigen binding site, i.e., capable of specifically binding to an antigen.
- the V H and the V L which form the antigen binding site can be in a single polypeptide chain or in different polypeptide chains.
- an Fv of the disclosure (as well as any protein of the disclosure) may have multiple antigen binding sites which may or may not bind the same antigen. This term shall be understood to encompass fragments directly derived from an antibody as well as proteins corresponding to such a fragment produced using recombinant means.
- the V H is not linked to a heavy chain constant domain (C H ) 1 and/or the V L is not linked to a light chain constant domain (C L ).
- exemplary Fv containing polypeptides or proteins include a Fab fragment, a Fab’ fragment, a F(ab’) fragment, a scFv, a diabody, a triabody, a tetrabody or higher order complex, or any of the foregoing linked to a constant region or domain thereof, e.g., C H 2 or C H 3 domain, e.g., a minibody.
- a “Fab fragment” consists of a monovalent antigen-binding fragment of an antibody, and can be produced by digestion of a whole antibody with the enzyme papain, to yield a fragment consisting of an intact light chain and a portion of a heavy chain or can be produced using recombinant means.
- a "Fab' fragment” of an antibody can be obtained by treating a whole antibody with pepsin, followed by reduction, to yield a molecule consisting of an intact light chain and a portion of a heavy chain comprising a V H and a single constant domain. Two Fab' fragments are obtained per antibody treated in this manner.
- a Fab’ fragment can also be produced by recombinant means.
- a “F(ab')2 fragment” of an antibody consists of a dimer of two Fab' fragments held together by two disulfide bonds, and is obtained by treating a whole antibody molecule with the enzyme pepsin, without subsequent reduction.
- a "Fab 2 " fragment is a recombinant fragment comprising two Fab fragments linked using, for example a leucine zipper or a C H 3 domain.
- a "single chain Fv” or “scFv” is a recombinant molecule containing the variable region fragment (Fv) of an antibody in which the variable region of the light chain and the variable region of the heavy chain are covalently linked by a suitable, flexible polypeptide linker.
- an "antigen binding fragment" of an antibody comprises one or more antibody variable domains of an intact antibody.
- antibody fragments include Fab, Fab', F(ab') 2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, half antibodies and multispecific antibodies formed from antibody fragments.
- mutant refers to a scFv (e.g., scFv mut ) which has undergone modification (e.g., deletion or truncation) of one or more amino acids using well known techniques to inactivate the receptor binding and/or functional activity of the scFv.
- modification e.g., deletion or truncation
- identity refers to the percentage number of amino acids that are identical or constitute conservative substitutions.
- identity may be determined using sequence comparison programs such as GAP (Deveraux et al, 1984, Nucleic Acids Research 12, 387-395), which is incorporated herein by reference. In this way sequences of a similar or substantially different length to those cited herein could be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.
- the terms “treating”, “treat” or “treatment” include administering a ADC described herein to thereby reduce or eliminate at least one symptom of a cancer or to slow progression of cancer. This term also encompasses treatment of a subject in remission to prevent or ameliorate a relapse or metastasis.
- Cancers that may be treated include those selected from the group consisting of breast cancer, lung cancer, a glioblastoma, prostate cancer, pancreatic cancer, colon cancer, colorectal cancer, head and neck cancer, mesothelioma, kidney cancer, ovarian, oesophageal, squamous cell carcinoma, triple negative breast cancer, and non-small cell lung cancer.
- an “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
- the desired result may be a therapeutic or prophylactic or imaging result or an imaging and therapeutic or prophylactic result.
- An effective amount can be provided in one or more administrations.
- the term "effective amount” is meant an amount necessary to effect treatment of a cancer as hereinbefore described.
- the term "effective amount” is meant an amount necessary to effect a change in a factor associated with a disease or condition as hereinbefore described.
- the effective amount may be sufficient to effect a beneficial change in the size of a solid tumour with for example, minimal systemic side effects.
- the effective amount may vary according to the disease or condition to be treated or factor to be altered and also according to the weight, age, racial background, sex, health and/or physical condition and other factors relevant to the mammal being treated. Typically, the effective amount will fall within a relatively broad range (e.g. a "dosage" range) that can be determined through routine trial and experimentation by a medical practitioner. Accordingly, this term is not to be construed to limit the disclosure to a specific quantity, e.g., weight or number of binding proteins.
- the effective amount can be administered in a single dose or in a dose repeated once or several times over a treatment period.
- a “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement of a particular disease or condition.
- a therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antigen binding protein -drug conjugate to elicit a desired response in the individual.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of the ADC are outweighed by the therapeutically beneficial effects.
- a therapeutically effective amount shall be taken to mean a sufficient quantity of ADC to treat a cancer such as a cancer associated with a solid tumor and metastasis.
- prophylactically effective amount shall be taken to mean a sufficient quantity of ADC to prevent or inhibit or delay the onset of cancer or the side effects of the cancer in a subject.
- subject shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and non-human primates. For example, the subject is a human.
- ADC Antibody Drug Conjugates
- the present inventors have developed an scFv-drug conjugate directed at activated platelets such as those found within the tumor microenvironment. They have determined its ability in vivo to concentrate potent cytotoxic agent within solid primary tumors and metastasis of the MDA-MB-231 murine metastatis model for triple negative breast cancer, and provide significant regression of primary tumors and prevention of metastases without systemic side effects.
- the present disclosure provides an Antibody-Fragment- Drug-Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and (ii) a drug which mediates its effect in the vicinity of the activated platelet conjugated in releasable from the (i).
- ADC Antibody-Fragment- Drug-Conjugate
- an Antibody-Fragment- Drug-Conjugate comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and (ii) a drug construct comprising a prodrug of a highly potent cytotoxic agent such as an auristatin or equivalent cytotoxic agent conjugated to (i).
- a site-directed enzymatic conjugation method using sortase A to catalyse the condensation reaction is used to conjugate an antibody variable domain with a C-terminal FPETG tag to a triglycine bridge or other spacer such as glycine at the N-terminus of a cytotoxic drug construct.
- the scFvGPIIb/IIIA- MMAE ADC displayed a band at 34kDa after western blotting ( Figure 2B) and the specific binding of the antibody variable domain (scFV) to activated platelets was retained after conjugation to MMAE by the present method (Figure 2C).
- the drug construct comprises a cleavable linker which, upon cleavage in the tumor microenvironment, releases the active cytotoxic drug which is able to induce tumor regression.
- the drug construct comprises a cleavable linker which, upon cleavage in the tumor microenvironment, releases the drug which is able to mediates its effect in the vicinity of the activated platelet.
- the drug construct comprises a cleavable linker which, upon cleavage in the tumor microenvironment, releases the drug which is able to induce tumor regression.
- the present application illustrates the use of a cathepsin cleavable contruct to activate the pro-drug.
- a pro-drug approach may not be required.
- Other illustrative microenvironment enzymes include MMPs and FAP.
- MMPs Since proteinases and peptidases are abundant in the tumor interstitial space, therapeutic nanosystems fused with peptides that are specific substrates of these enzymes can be designed to control the release of therapeutic agents within the tumor microenvironment.
- MMPs with an elevated expression in tumor ECM, are crucial in tumor progression. Therefore, making use of MMP-cleavable sequences achieves drug release or active site exposure.
- the substrate peptide for MMP-2 is GPLGIAGQ; this sequence is cleaved into GPLG and IAGO by MMP-2.
- Fibroblast activation protein-a is another accessible protease that is specifically expressed on the surface of CAFs, a major cellular component in the tumor microenvironment.
- FAP-a selectively cleaves the sequence GPAX (X designates any amino acid) between proline, and alanine (Ji et ah, Angew Chem Int Ed Engl 55:1050-1055, 2016; Qin et al Molecular Pharmacology 92(3): 219- 231).
- an Antibody-Fragment- Drug-Conjugate comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet-specific GPIIb/IIIa and part of a C-terminal sortase A sequence conjugated to the N-terminus of (ii) a drug construct comprising an N-terminal nucleophilic group (e.g.
- glycine or polyglycine e.g., GGG sequence linked via a peptidase cleavable linker and optionally a spacer to a cytotoxic agent such as an auristatin or equivalent cytotoxic agent.
- an Antibody-Fragment- Drug-Conjugate comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet-specific GPIIb/IIIa and part of a C-terminal sortase A conjugated to the N-terminus of (ii) a drug construct comprising an N-terminal polyglycine (e.g. GGG) sequence linked via a cleavable linker and a spacer to a cytotoxic agent such as an auristatin or equivalent cytotoxic agent.
- ADC Antibody-Fragment- Drug-Conjugate
- the present disclosure is of an ADC comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet-specific GPIIb/IIIa and a C-terminal sortase A recognition sequence and (ii) a cathepsin B dependent cytotoxic prodrug comprising an N-terminal polyglycine (e.g. GGG) sequence linked via a cathepsin B cleavable peptide linker to an auristatin or equivalent cytotoxic agent.
- a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet-specific GPIIb/IIIa and a C-terminal sortase A recognition sequence
- a cathepsin B dependent cytotoxic prodrug comprising an N-terminal polyglycine (e.g. GGG) sequence linked via a cathepsin B cleavable peptide linker to an auristatin or equivalent cytotoxic agent
- the antibody variable domain binds an epitope of GPIIb/IIIa recognised by a scFv consisting of a sequence set forth in SEQ ID NO: 1.
- the antibody variable domain comprises a complementary determining region (CDR) of the heavy chain variable region (V H ) having the sequence of SEQ ID NO:2 and/or a CDR of the light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 3.
- CDR complementary determining region
- the antibody variable domain comprises a heavy chain variable region (VH) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 2 and a light chain variable region (VL) comprising a sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 3.
- VH heavy chain variable region
- VL light chain variable region
- the antibody variable domain comprises an amino acid sequence which is at least 90% identical to a sequence set forth in SEQ ID NO: 1.
- antibody variable domain variants encompassed comprise one to four or two to eight amino acid substitutions and retain high affinity specific binding to activated GPIIb/IIIa.
- sequence identity refers to the extent that sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid basis over a window of comparison.
- a "percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.
- the identical nucleic acid base e.g., A, T, C, G, I
- the identical amino acid residue e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys,
- sequence identity are understood to mean the “match percentage” calculated by the DNASIS computer program (Version 2.5 for windows; available from Hitachi Software engineering Co., Ltd., South San Francisco, California, USA) using standard defaults as used in the reference manual accompanying the software. Conservative substitutions known in the art may also be assessed and included in the percent identity calculation. As known in the art, even non-conservative substitutions within CDR regions are tolerated and can be routinely tested.
- the antibody variable domain is derived from a human scFv library.
- the antibody variable domain is scFVGPiib/iiia that binds only to the activated form of platelet- specific GPIIb/IIIa having the amino acid sequence set out in SEQ ID NO:l.
- the ADC comprises the Val-Citrulline cleavable linker.
- the ADC comprises a spacer wherein the spacer is a self immolative spacer, such as a para-aminobenzylalcohol (PABA) spacer.
- PABA para-aminobenzylalcohol
- the ADC comprises (i) a fusion protein comprising scFV GPiib/iiia and a C-terminal sortase A recognition sequence and (ii) an N-terminal polyglycine sequence linked via a cleavable linker and immolative spacer to MMAE.
- cytotoxic agent includes cytotoxic agents that are active at picomolar concentrations.
- the cytotoxic agent is a mitotic inhibitor or an anti-tumor antibiotic or a plant alkaloid.
- Illustrative mitotic inhibitors include a dolastatin, an auristatin, a maytansinoid, and a plant alkaloid.
- auristatin refers to a family of antimitotic agents. Auristatin derivatives are also included within the definition of the term "auristatin”.
- auristatins include, but are not limited to, auristatin E (AE), monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), and synthetic analogs of auristatin.
- Maytansinoids include, for example, DM1, DM2, DM3, and DM4.
- anti-tumor antibiotics are selected from the group consisting of an actinomycine (e.g., PBD), an anthracycline, a calicheamicin, and a duocarmycin.
- the chemotherapeutic agent is selected from a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
- Classes of chemotherapeutic agents include, but are not limited to: alkyating agents, antimetabolites, spindle poison plant alkaloids, cytoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors.
- Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy.
- chemotherapeutic agents include: erlotinib docetaxel), 5-FU, gemcitabine, cisplatin, carboplatin, paclitaxel, trastuzumab temozolomide, tamoxifen, doxorubicin and rapamycin.
- chemotherapeutic agents include: oxaliplatin imatinib mesylate, Mek inhibitor, PI3K inhibitor, fulvestrant, leucovorin), rapamycin, lapatinib, lonafarnib sorafenib gefitinib irinotecan tipifarnib, albumin-engineered nanoparticle formulations of paclitaxel vandetanib chloranmbucil, AG1478, AG1571, temsirolimus, pazopanib canfosfamide, thiotepa and cyclosphosphamide alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophospho
- chemotherapeutic agent or “drug” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands; (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a l,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras,
- SERMs selective
- Immune modulators are an important class of compounds that are directed to activated platelets in concentrated form by the present invention. Examples include check point inhibitors, TLR agonists.
- chemotherapeutic agent therapeutic antibodies such as alemtuzumab, bevacizumab, cetuximab, panitumumab rituximab pertuzumab trastuzumab tositumomab and the antibody drug conjugate, gemtuzumab.
- Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
- a variety of radionuclides are available for the production of radioconjugated antibodies.
- the antibody variable domain, fusion protein or ADC as described herein comprises a detectable label.
- detectable labels are suitable for imaging and tracing tumors.
- Detectable labels include fluorescent compounds such as fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-l-napthalenesulfonyl chloride, phycoerythrin and the like.
- Detectable labels include detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. As well understood, detectable enzyme are detected by adding enzyme substrates to produce a detectable reaction product.
- An antibody or ADC may also be labelled with biotin, and detected through indirect measurement of avidin or streptavidin binding.
- the antibody variable domain is conjugated to an imaging agent/label/dye known in the art.
- imaging agents include, but are not limited to, MRI contrast agents such as Gd, Mn and F etc, a radiolabel, radiotracer, an enzyme, a fluorescent label or dye a luminescent label, a bioluminescent label, a magnetic label, and biotin.
- Contrast agents for molecular imaging of cancer using a range of distinct molecular imaging modalities are provided.
- Illustrative modalities include without limitation, MRI, fluorescence imaging (e.g. Cy7 and FLECT imaging) and molecular imaging via for example PET/CT (e.g. 64 Cu) and ultrasound (e.g., ultrasound enhancing microbubbles such as streptavidin-coated microbubbles, and photoacoustic imaging).
- the ADC as described herein comprises a 1 : 1 ratio of antibody variable domain to pro-drug.
- the ratio in the ADC or composition is about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.
- vectors comprising the polynucleotide sequences encoding the binding proteins of the present invention are contemplated.
- Illustrative polynucleotide sequences are described in Figure 8 and 9 and in the sequence listing, or sequences having at least 90%, 95% or 99% sequence identity.
- Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, inter alia, BHK, VERO, HT1080, 293, 293T, 293F, RD, COS-7, CHO, Jurkat, HUT, SUPT, C8166, HepG2, MOLT4/clone8, MT-2, MT-4, H9, PM1, CEM, myeloma cells (e.g., SB20 cells) and CEMX174, HEK293T, NSO, SP2 cells, HeLa cells, A549 cells, 3T3 cells, and a number of other cell lines.
- ATCC American Type Culture Collection
- Other cells that may be used include insect cell lines, such as Sf9cells, avian, amphibian cells, plant cells, yeast and fungal yeast cells.
- a non mammalian cell may be employed such as a yeast cell, such as Hansenula polymorpha. Such cells are useful for providing controlled levels of expression.
- Vectors available for cloning and expression in host cell lines are well known in the art, and include but are not limited to vectors for cloning and expression in mammalian or yeast cell lines, vectors for cloning and expression in bacterial cell lines, vectors for cloning and expression in phage and vectors for cloning and expression insect cell lines.
- the fusion proteins can be recovered using standard protein purification methods.
- the composition comprises an Antibody-Fragment-Drug-Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and (ii) a drug construct comprising a prodrug of a highly potent cytotoxic agent such as an auristatin or equivalent cytotoxic agent conjugated to
- ADC Antibody-Fragment-Drug-Conjugate
- the composition comprises an Antibody-Fragment-Drug- Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and part of a C-terminal sortase A sequence conjugated to the N-terminus of (ii) a drug construct comprising an N-terminal glycine sequence linked via a cleavable linker and optionally a spacer to a cytotoxic agent such as an auristatin or equivalent cytotoxic agent.
- ADC Antibody-Fragment-Drug- Conjugate
- the composition comprises a pharmacologically or physiologically acceptable diluent and/or carrier.
- pharmaceutically acceptable carrier or diluent is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction.
- Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emusifying agents, pH buffering agents, preservatives, and the like.
- a variety of acceptable carriers known in the art may be used, as for example described in Remington's Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991).
- the composition comprises ADC wherein the ratio of antibody variable domain to pro-drug is substantially 1:1.
- each antibody or each antibody variable domain is conjugated to 2, 3, 4, 5, 6, 7, 8, 9, or 10 drug molecules.
- sortase A mediated conjugation of the drug construct to the fusion protein comprising the antibody variable domain produces an essentially homogeneous ADC with substantially no undesired species having heterogenous numbers of drug to antibody ratios. This is useful for both medical and imaging applications.
- composition comprising the ADC as described herein is for use in (or used for) medical therapy or medical imaging.
- the ADC is preferably administered in a therapeutically effective amount.
- the actual amount administered and the rate and time-course of administration will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc. is within the responsibility of general practitioners or specialists and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington’s Pharmaceutical Sciences, supra.
- the binding protein is administered parenterally, such as subcutaneously or intravenously.
- the binding protein administered intravenously.
- Formulation of a ADC to be administered will vary according to the route of administration and formulation (e.g., solution, emulsion, capsule) selected.
- An appropriate pharmaceutical composition comprising an ADC to be administered can be prepared in a physiologically acceptable carrier as discussed herein.
- suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
- aqueous carriers include water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution and glycine.
- Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, l6th Edition, Mack, Ed. 1980).
- the compositions can optionally contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents and toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.
- the ADC can be stored in the liquid stage or can be lyophilized for storage and reconstituted in a suitable carrier prior to use according to art-known lyophilization and reconstitution techniques.
- the present disclosure also provides for the use of a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet-specific GPIIb/IIIa and a C-terminal sortase A recognition sequence in the preparation of a cancer imaging agent.
- the disclosure provides an fusion protein comprising the antibody variable domain as described herein and a detectable label suitable for imaging.
- the disclosure provides a vector or host cell comprising a polynucleotide sequence capable of expressing the fusion protein comprising the fusion proteins comprising the antibody variable domain as described herein.
- the antibody variable domain is conjugated to a bifunctional sarcophagine chelator, MeCOSar and labelled with copper- 64 .
- cancer cells induce activation and can be imaged using ScFv GPiib/ ni a -Cy7-MMAE in vitro and in vivo.
- imaging can be carried out using the antibody variable domain linked to a detectable agent.
- the antibody variable domain is conjugated to a detectable label via sortase A mediated conjugation. Fusion proteins comprising the antibody variable domain and a sortase A recognition sequences can conveniently be produce recombinantly.
- One non-limiting illustrative cancer imaging agent is ScFv GPiib/ ni a -Cy7.
- Detectable labels include fluorescent compounds such as fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-l-napthalenesulfonyl chloride, phycoerythrin and the like.
- Detectable labels include detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. As well understood, detectable enzyme are detected by adding enzyme substrates to produce a detectable reaction product.
- An antibody or ADC may also be labelled with biotin, and detected through indirect measurement of avidin or streptavidin binding.
- the antibody variable domain is conjugated to an imaging agent/label/dye known in the art.
- imaging agents include, but are not limited to, a radiolabel, radiotracer, an enzyme, a fluorescent label or dye a luminescent label, a bioluminescent label, a magnetic label, and biotin.
- Contrast agents for molecular imaging of cancer using a range of distinct molecular imaging modalities include, fluorescence imaging (e.g. Cy7) and molecular imaging via for example PET/CT (e.g. 64 Cu) and ultrasound (e.g., ultrasound enhancing microbubbles such as streptavidin-coated microbubbles)
- negative control imaging agents include mutated antibody variable domains.
- Illustrative controls include scFvmut-detectable label formats.
- Cancer imaging agents and controls as described herein may be provided in the form of kits for cancer imaging. Kits are optionally provided with instructions for use in cancer imaging.
- Kits comprising vectors or host cells expressing a fusion protein comprising the antigen variable domain as described herein and a sortase A recognition sequence are contemplated.
- Vectors or host cells expressing a negative control imaging agents include mutated antibody variable domains and a sortase A recognition sequence.
- the present disclosure enables the use of a composition comprising the ADC as described herein in, or in the preparation of a medicament for, the treatment of cancer including reduction of solid tumors and reduced metastasis in a subject diagnosed with cancer.
- the composition comprises an Antibody- Fragment-Drug-Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and (ii) a drug construct comprising a prodrug of a highly potent cytotoxic agent such as an auristatin or equivalent cytotoxic agent conjugated to (i).
- ADC Antibody- Fragment-Drug-Conjugate
- the composition comprises an Antibody-Fragment-Drug- Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and part of a C-terminal sortase A sequence conjugated to the N-terminus of (ii) a drug construct comprising an N-terminal glycine sequence linked via a cleavable linker and optionally a spacer to a cytotoxic agent such as an auristatin or equivalent cytotoxic agent.
- ADC Antibody-Fragment-Drug- Conjugate
- FIG. 1 An illustrative ADC is shown in Figure 1 being produced by sortase A mediated site specific biological conjugation and then cleaved by cathepsin B to release the active cytotoxic agent MMAE.
- tumor microenvironment is pre-identified as comprising abundant activated platelets.
- the cancer is selected from the group consisting of breast cancer, lung cancer, a glioblastoma, prostate cancer, pancreatic cancer, colon cancer, colorectal cancer, head and neck cancer, mesothelioma, kidney cancer, ovarian, oesophageal, squamous cell carcinoma, triple negative breast cancer, and non- small cell lung cancer.
- the disclosure enables a method of treating cancer and of reducing metastasis comprising administering an effective amount of a composition comprising an ADC as described herein to a subject with cancer.
- the composition comprises an Antibody-Fragment-Drug-Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and (ii) a drug construct comprising a prodrug of a highly potent cytotoxic agent such as an auristatin or equivalent cytotoxic agent conjugated to (i).
- ADC Antibody-Fragment-Drug-Conjugate
- the composition comprises an Antibody-Fragment-Drug- Conjugate (ADC) comprising: (i) a fusion protein comprising an antibody variable domain that binds only to the activated form of platelet- specific GPIIb/IIIa and part of a C-terminal sortase A sequence conjugated to the N-terminus of (ii) a drug construct comprising an N-terminal polyglycine (e.g. GGG) sequence linked via a cleavable linker and optionally a spacer to a cytotoxic agent such as an auristatin or equivalent cytotoxic agent.
- ADC Antibody-Fragment-Drug- Conjugate
- the effective amount concentrates therapeutic doses of cytotoxic agent within the tumor and at sites of metastasis.
- the same amount of ADC comprising a non-binding (mutant) antibody provides substantially no therapeutic/cytotoxic/tumor/metastasis reduction activity.
- the effective amount also has substantially no or minimal off-target side effects on haematological parameters, liver function and renal function comparable to vehicle control.
- the optimum concentration of the active ingredient(s) in the chosen medium can be determined empirically, according to procedures known to the skilled artisan, and will depend on the ultimate pharmaceutical formulation desired.
- the composition comprises an effective amount of the binding protein.
- the composition comprises a therapeutically effective amount of the binding protein.
- the composition comprises a prophylactically effective amount of the binding protein.
- the dosage should not be so large as to cause adverse side effects.
- the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.
- the dosage can be adjusted by the individual physician in the event of any complication.
- Dosages can vary from about 0.01 mg/kg to about 5 mg/kg, or 0.01 -5 mg/kg or 0.1 - 2 mg/kg or 0.03 - 2 mg/kg, or 0.05 mg/kg to about 100 mg/kg, e.g., from about 0.1 mg/kg to about 50 mg/kg, such as, from about 0.5 mg/kg to about 20 mg/kg or 2 mg/kg to about 5 mg/kg, in one or more dose administrations daily for one or several days or weekly or every four days for three to six weeks or more. Please advise if a different dose is preferred.
- the ADC is administered at an initial (or loading) dose which is higher than subsequent (maintenance doses).
- the ADC is administered at an initial dose of between about 1 mg/kg to about 50mg/kg.
- the binding protein is then administered at a maintenance dose of between about O.OOOlmg/kg to about lOmg/kg.
- the maintenance doses may be administered every 7- 35 days, such as, every 7 or 14 or 28 days.
- a dose escalation regime is used, in which a ADC is initially administered at a lower dose than used in subsequent doses.
- multiple doses in a week may be administered.
- increasing doses may be administered.
- a subject may be retreated with ADC, by being given more than one exposure or set of doses, such as at least about two exposures of the binding protein, for example, from about 2 to 60 exposures, and more particularly about 2 to 40 exposures, most particularly, about 2 to 20 exposures.
- any retreatment may be given after imaging with the labelled antibody variable domain protein to confirm the presence of activated platelets in the tumor.
- any retreatment may be given at defined intervals.
- subsequent exposures may be administered at various intervals, such as, for example, about 24-28 weeks or 48-56 weeks or longer.
- such exposures are administered at intervals each of about 24-26 weeks or about 38-42 weeks, or about 50-54 weeks.
- given the ability to administer an effective dose without substantial systemic side effects means that the patient may tolerate long term treatment, if required.
- the ADC is administered systemically and displays minimal systemic side effects.
- the ADC is concentrated in the tumor microenvironment by binding of the antibody variable domain to activated platelets within the tumor microenvironment and wherein the cytotoxic agent is activated in the tumor microenvironment by endogenous cleavage of the ADC within the tumor microenvironment.
- Subjects contemplated in the present description include patients including humans or animals including laboratory animals or art accepted test animals. Patients include human subjects in need of treatment or prophylaxis.
- the ADC is administered in combination with an additional cytotoxic or therapeutic agent.
- the additional agent is selected from the group consisting of an anti-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an alkylating agent, an anti-angiogenic agent, an anti-metabolite, a boron-containing agent, a chemoprotective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.
- scFv single-chain antibody
- the scFv was conjugated to three different contrast agents; Cy7 for fluorescence imaging, 64 Cu for PET imaging and microbubbles for ultrasound imaging. This novel approach provides holds promise as a universal and flexible diagnostic method for the detection and imaging of cancer.
- a subject is screened using the binding protein-imaging agent and, if positive, is treated with the binding protein-therapeutic agent.
- Theranostic methods are enabled comprising (i) screening for cancer by detection with the binding agent-imaging agent conjugate, followed by (ii) treatment with the binding agent-therapeutic drug conjugate as described and enabled herein.
- scFv -Biotin The generation of biotinylated scFv GPiib/iiia and scFv mut has been described previously. Both scFvs were sub-cloned into the AviTagTM containing pAC6 vector system, the DNA was then transformed into electrocompetent cell E. coli EVB101 (Avidity LLC) by electroporation. In vivo biotinylation was performed according to the manufacturer’s instruction producing the attachment of one biotin molecule on every scFv.
- Alternative tags are known in the art, such as a spycatcher/spyTag system.
- the resultant scFv-BCN was further conjugated to an azide-NIR dye (azide-Cyanine 7 dye) via copper-free click reaction to generate the FFECT tracer.
- azide-NIR dye azide-Cyanine 7 dye
- Excess free dye was dialysed in PBS and the purified scFv- Cy7 was analyzed on a SDS-PAGE gel and NIR signal from the band of interest was confirmed using the Odyssey Imager.
- 64 Cu Production and scFv Radiolabeling - 64 CuCl 2 produced by the 64 Ni(p,n) 64 Cu reaction was obtained from the Austin Health Centre for PET. The solution was provided with a radionuclidic purity, tested using gamma ray spectrometry of >99% and a radiochemical purity, tested using HPFC of >95%.
- the scFv used for PET/CT imaging were conjugated to a sarcophagine chelator, MeCOSar (Clarity Pharmaceuticals) 21,22 .
- MeCOSar MeCOSarity Pharmaceuticals
- diethylenetriaminepentaacetic acid (10 pF, 10 mM) was added to the mixture and incubated for a further 5 min at room temperature. Samples were washed twice with PBS in spin columns (Millipore, cutoff 10,000 MWCO) and resuspended in PBS at a final concentration of 0.2 mg/mL to produce scFv GPiib/ ni a - 64 Cu or scFv mut - 64 Cu.
- Cancer Cell Lines -Human cancer cell lines SKBr3, MDA-MB-231, Ramos and HT- 1080 were cultured in RPMI media (GIBCO® #21870) supplemented with 10% (v/v) FBS (Invitrogen), 100 ET/ml penicillin, and 0.1 mg/ml streptomycin at 37°C in a 5% C0 2 humidified atmosphere.
- Preparation of Human Washed Platelets -Fresh blood was drawn from informed healthy volunteers who had not taken anti-platelet drugs at least two weeks prior to venesection. Blood was collected into acid citrate dextrose (ACD; 85 mM sodium citrate, 72.9 mM citric acid, 110 mM D-glucose, 70 mM theophylline) (at a ratio of ACD:blood of 1:6) and supplemented with apyrase 0.005 U/mF and enoxaparin 20 U/mF. Whole blood was centrifuged at 200 g for 10 min. Platelet rich plasma (PRP) was obtained and then centrifuged at l700g for 7 min.
- ACD acid citrate dextrose
- PRP Platelet rich plasma
- PPP platelet poor plasma
- platelet washing buffer pH 6.5; 4.3 mM K 2 HP0 4 ; 4.3 mM Na 2 HP0 4 ; 24.3 mM NaH 2 P0 4 ; NaCl 0.113 M; 5.5 mM D-glucose; 10 mM theophylline
- enoxaparin 20 U/mL
- apyrase O.OlU/mL
- washed platelets were resuspended in Tyrode’s buffer (pH 7.2- 7.4; 12 mM NaHCOs; Hepes 10 mM; NaCl 0.137 M; KCL 27 mM; D-glucose 55 mM) containing 1 mM CaCl and apyrase 0.02 U/mL.
- Tumour Xenograft Model - 5-6 weeks old female BALB/c nude mice were purchased from the Animal Resources Centre, Canningvale. To establish tumour xenografts, mice were injected subcutaneously with exponentially growing SKBr3, MDA-MB-231, Ramos or HT-1080 cells (2.0 x 10 6 cells per mouse) in 0.3 ml of matrigel (BD Biosciences #356234) into the left flank region. Tumours were left to grow and measured daily until reaching a diameter of approximately 4 mm, which usually appears 2-3 weeks post xenograft cell injection.
- ROI region-of-interest
- MFI mean fluorescence intensity
- PET Imaging In vivo PET Imaging -Animals were injected intravenously with 20 pg scFv GPiib/iiia - 64 Cu or scFv mut - 64 Cu. Tracer was allowed to circulate for two hours. Animals were anesthetized with ketamine (50 mg/kg; Parnell Laboratories) and xylazine (10 mg/kg; Troy Laboratories) and placed in the PET/CT scanner supplied with continuous 0 2 and 2% isofluorane. PET/CT imaging was performed using a NanoPET/CT in vivo Preclinical Imager (Mediso) with a 30 min PET acquisition time, and coincidence mode of 1:3.
- Tumour sections were stained overnight with a polyclonal rabbit anti-CD4l antibody (Abeam #ab63983), and detected with an Alexa Fluor 647 labeled anti-rabbit antibody (Life Technologies #A-2l245), counterstained with Hoechst® (Thermo Fisher Scientific #33342) and visualized using the Nikon Alr Plus Confocal Microscope, 60x oil objective.
- the central element of the imaging study is the ability to target and image activated platelets as a general component of the tumour microenvironment, thereby defining a novel non-invasive technique to diagnose and localize tumours in vivo.
- the results demonstrate the feasibility of Cy7, 64 Cu and microbubbles as conjugates to the scFv GPiib/ ni a for imaging tumours in vivo.
- the ability to use the recombinant single-chain antibody scFv GPiib/ ni a which specifically binds to activated platelets have been characterized extensively in previous in vivo studies, and thus provides a solid foundation to conclude based on the studies described herein that activated platelets can serve as a marker of the tumour microenvironment.
- the specificity and sensitivity of the scFv GPiib/ ni a allowed strong targeting to activated platelets and thus represents a unique foundation of this molecular target as a unique approach for tumour imaging.
- imaging of activated platelets in cancer can be used as an auxiliary imaging strategy to allow the accurate delineation of the anatomic distribution of tumours..
- the scFvG Piib/ ni a illustrates the important role for targeting activated platelets in tumor therapy and the use of activated platelet- specific antibody variable domain targeted drug delivery as means to enhance the efficacy, whilst minimizing the systemic toxicity of chemotherapy.
- the protein comprising an antibody variable domain of the present disclosure comprises a binding region that is an inhibitor of GPIIb/IIIa receptor function and/or activity.
- the binding region specifically binds an epitope on GPIIb/IIIa recognised by a scFv consisting of a sequence set forth in SEQ ID NO: 1.
- the binding region competitively inhibits binding of a scFv consisting of a sequence set forth in SEQ ID NO: 1 to an epitope on GPIIb/IIIa.
- the binding region comprises an antibody variable region, e.g., is an antibody or an antibody fragment that binds to GPIIb/IIIa.
- the antibody variable region binds specifically to activated GPIIb/IIIa.
- Suitable antibodies and proteins comprising variable regions thereof are known in the art and/or described herein.
- the binding protein comprises a binding region, wherein the binding region is a protein comprising a Fv.
- the protein comprises a single chain Fv fragment (scFv).
- scFv Single Chain Fv
- Fragments comprise VH and VL regions in a single polypeptide chain and a polypeptide linker between the VH and VL which enables the scFv to form the desired structure for antigen binding (i.e., for the VH and VL of the single polypeptide chain to associate with one another to form a Fv).
- the linker comprises the sequence SSGS.
- the present disclosure also contemplates a disulfide stabilized Fv (or diFv or dsFv), in which a single cysteine residue is introduced into a FR of VH and a FR of VL and the cysteine residues linked by a disulfide bond to yield a stable Fv.
- a dimeric scFv i.e., a protein comprising two scFv molecules linked by a non-covalent or covalent linkage, e.g., by a leucine zipper domain (e.g., derived from Fos or Jun).
- two scFvs are linked by a peptide linker of sufficient length to permit both scFvs to form and to bind to an antigen, e.g., as described in US20060263367.
- a humanized antibody or fragment thereof e.g., a protein comprising a human like variable region, which includes CDRs from an antibody from a non-human species (e.g., mouse or rat or non-human primate) grafted onto or inserted into FRs from a human antibody (e.g., produced by methods described in US5225539, US6054297, US7566771 or US5585089) • a human antibody or fragment thereof, e.g., antibodies having variable and, optionally, constant antibody regions found in humans, e.g. in the human germline or somatic cells or from libraries produced using such regions.
- the "human” antibodies can include amino acid residues not encoded by human sequences, e.g. mutations introduced by random or site directed mutations in vitro (e.g., produced by methods described in US5565332) and affinity matured forms of such antibodies.
- a synhumanized antibody or fragment thereof e.g., an antibody that includes a variable region comprising FRs from a New World primate antibody variable region and CDRs from a non-New World primate antibody variable region (e.g., produced by methods described in W02007019620).
- a primatized antibody or fragment thereof e.g., an antibody comprising variable region(s) from an antibody generated following immunization of a non-human primate (e.g., a cynomolgus macaque) (e.g., produced by methods described in US6113898).
- a non-human primate e.g., a cynomolgus macaque
- a chimeric antibody or chimeric antigen binding fragment e.g., an antibody or fragment in which one or more of the variable domains is from a particular species (e.g., murine, such as mouse or rat) or belonging to a particular antibody class or subclass, while the remainder of the antibody or fragment is from another species (such as, for example, human or non-human primate) or belonging to another antibody class or subclass (e.g., produced by methods described in US6331415; US5807715; US4816567 and US4816397).
- a chimeric antibody or chimeric antigen binding fragment e.g., an antibody or fragment in which one or more of the variable domains is from a particular species (e.g., murine, such as mouse or rat) or belonging to a particular antibody class or subclass, while the remainder of the antibody or fragment is from another species (such as, for example, human or non-human primate) or belonging to another antibody class or subclass (e.g., produced by methods described
- a deimmunized antibody or antigen binding fragment thereof e.g., antibodies and fragments that have one or more epitopes, e.g., B cell epitopes or T cell epitopes removed (i.e., mutated) to thereby reduce the likelihood that a subject will raise an immune response against the antibody or protein (e.g., as described in W02000034317 and W02004108158).
- epitopes e.g., B cell epitopes or T cell epitopes removed (i.e., mutated) to thereby reduce the likelihood that a subject will raise an immune response against the antibody or protein (e.g., as described in W02000034317 and W02004108158).
- a bispecific antibody or fragment thereof e.g., an antibody comprising two types of antibodies or antibody fragments (e.g., two half antibodies) having specificities for different antigens or epitopes (e.g., as described in US5731168).
- Additional exemplary antibody fragments for use in the present disclosure are described herein or known in the art and include:
- single-domain antibodies domain antibody or dAb
- a single polypeptide chain comprising all or a portion of the heavy chain variable domain of an antibody.
- a diabody, triabody, tetrabody or higher order protein complex e.g., as described in W098/044001, W094/007921 see also Kim et al Mol Cancer Ther 2008; 7(8) 2008).
- a half-antibody or a half-molecule e.g., a protein comprising a single heavy chain and a single light chain.
- the present disclosure also contemplates other antibodies and antibody fragments, such as:
- heteroconjugate proteins e.g., as described in US4676980;
- heteroconjugate proteins produced using a chemical cross-linker, e.g., as described in US4676980;
- the present disclosure provides an ADC comprising one or more linkers.
- the present disclosure contemplates various forms of covalent and non- covalent linkages.
- the regions can be linked by a chemical or flexible or peptide linker.
- Peptide linkers may comprise between 2 and 30 amino acids in length. Linkers may comprise non-naturally occurring amino acids.
- the linker sequence is at least about 3 amino acids in length.
- a linker comprises the sequence (Ala) 3 .
- a "flexible" linker is an amino acid sequence which does not have a fixed structure (secondary or tertiary structure) in solution. Such a flexible linker is therefore free to adopt a variety of conformations.
- Flexible linkers suitable for use in the present disclosure are known in the art. Flexible linkers are also disclosed in WO1999045132.
- the linker may comprise any amino acid sequence that does not substantially hinder interaction of the binding region with its target.
- Preferred amino acid residues for flexible linker sequences include, but are not limited to, glycine, alanine, serine, threonine proline, lysine, arginine, glutamine and glutamic acid.
- the linker is a rigid linker.
- a "rigid linker” refers to a linker having limited flexibility.
- the relatively rigid linker comprises the sequence (EAAAK) n , where n is between 1 and 3.
- the value of n can be between 1 and about 10 or between about 1 and 100.
- n is at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10.
- n is less than 100.
- n is less than 90, or less than about 80, or less than about 60, or less than about 50, or less than about 40, or less than about 30, or less than about 20, or less than about 10.
- a rigid linker need not completely lack flexibility.
- the linker is a cleavable linker.
- the linker comprises a cleavage site for a peptidase.
- the linker comprises a cleavage site for urokinase, pro-urokinase, plasmin, plasminogen, TGFP, staphylokinase, Thrombin, a coagulation factor (e.g., Factor IXa, Factor Xa) or a metalloproteinase, such as an interstitial collagenase, a gelatinase or a stromelysin.
- Exemplary cleavable linkers are described in US6,004,555, US5,877,289, US6,093,399 and US5,877,289.
- linkers include hydrazone linkers, disulphide linkers, peptide linkers and beta-glucuronide linkers.
- Stable conjugation of antibody or smaller antibody fragments known in the art to drugs can be achieved using various different approaches and methods.
- Chemical strategies include amide linkages, Schiff base linkages, hydrazone formation (unstable in acidic pHs), thiols and click reaction technologies resulting in for example stable l,2,3-triaazole linkages.
- specific conjugation strategies have been developed with recombinant antibody fragments, these include streptavidin-biotin links, peptide bonds formed by sortase A peptidase between LPXTG and an N-terminal glycine, other engineer able site specific modifications include sulfhydryl groups His6- tags, N-terminal serine/threonine, and the above mentioned enzyme tags/SNAP tags.
- SNAP tag technology may be used to conjugate (covalently couple) a single chain fragment variable drugs such as auristatin F via benzylguanine (BG).
- AURIF is a BG-modified version of MMAF suitable for SNAP-tag coupling.
- the SNAP-tag is an engineered version of the human DNA repair enzyme 06-alky lguaninc-DNA- alkyltransferase, which allows the covalent coupling of BG-modified components with a defined 1:1 stoichiometry.
- ADCs may employ chemical linkage to cysteine or lysine residues in mAbs, resulting in a heterogeneous mixture of products with a undefined drug-to-antibody ratio (DAR) and varying conjugation sites.
- DAR drug-to-antibody ratio
- SNAP- tag and similar strategies can overcome these limitations.
- the binding protein of the disclosure is conjugated to a detectable label, for example, a fluorescent label or a radioactive label.
- the labeled protein and the test binding protein are then mixed and contacted with GPIIb/IIIa or a peptide comprising an epitope thereof.
- the level of labeled protein is then determined and compared to the level determined when the labeled protein is contacted with the GPIIb/IIIa or the peptide comprising an epitope thereof in the absence of the binding protein. If the level of labeled protein is reduced in the presence of the binding protein compared to the absence of the binding protein, the binding protein competitively inhibits binding of the scFv.
- the epitope bound by a protein described herein is mapped.
- Epitope mapping methods will be apparent to the skilled artisan. For example, a series of overlapping peptides spanning the GPIIb/IIIa sequence or a region thereof comprising an epitope of interest, for example, peptides comprising 10 to 15 amino acids are produced. The binding protein is then contacted to each peptide or a combination thereof and the peptide(s) to which it binds determined. This permits determination of peptide(s) comprising the epitope to which the binding protein binds. If multiple non-contiguous peptides are bound by the protein, the protein may bind a conformational epitope.
- amino acid residues within GPIIb/IIIa are mutated, for example, by alanine scanning mutagenesis, and mutations that reduce or prevent protein binding are determined. Any mutation that reduces or prevents binding of the binding protein is likely to be within the epitope bound by the protein.
- the present disclosure includes the following non-limiting Examples.
- scFv was then subcloned into a pSectag 2A vector (Invitrogen) for expression in human embryonic kidney (HEK) cells (Invitrogen), see Hohmann et al. Blood 2013: 12l (6):3067-3075.
- Sortase A is used to induce an enzymatic reaction used for the conjugation of the scFv, carrying an LPETG sequence to MMAE which was produced carrying a triple glycine sequence.
- Sortase A a transpeptidase cloned from Staphylococcus aureus was produced and purified as previously described, see Wang et al. Theranostics 20l6;6(5):726-738. All proteins (scFvs and sortase A) contains a 6x His-tag, which was used for purification with nickel-based affinity chromatography (Invitrogen).
- the purified scFv-Cy7- MMAE was then analyzed by SDS-PAGE gel and the protein and near-infrared signal from the band of interest was confirmed using the Odyssey Imager. Additionally, western blot was performed with rabbit anti-MMAE antibody (Levena Biopharma), detected with an anti-rabbit HRP antibody (Cell Signalling) to confirm conjugation of MMAE to the scFv.
- Flow cytometry was performed using a FACS Fortessa scanner (BD Biosciences, Franklin Lakes, NJ, United States). Results were analyzed using the Flowlogic software.
- platelet rich plasma was incubated with the cancer cell lines MDA-MB-231, HT29, HT1080 and PC3 for 6 hours at 37°C.
- ADP-activated platelet rich plasma was incubated with the cancer cells for 6 hours at 37°C.
- the cancer cell and platelet (resting/ ADP-activated platelets) mixtures were then stained with an anti-CD4l-PE monoclonal antibody (BD Biosciences, Franklin Lakes, NJ, United States) and scFv GPiib/iiia or scFv mut binding was detected by an anti-V5-FITC monoclonal antibody (Abeam, Cambridge, United Kingdom). Flow cytometry and analysis was performed as described above.
- Cancer Cell Lines A metastatic variant of the MDA-MB-231 triple-negative breast adenocarcinoma cell line (a kind gift from Dr Zhou Ou, Fudan University Shanghai Cancer Center, China) was transduced with a lentiviral vector containing codon- optimized firefly luciferase-mCherry under the control of the ubiquitin-C promoterF 23,24 Li et al. European Journal of Cancer 2006;42(18):3274-3286 and Le et al. Nature Communications 2016;7: 10634) and was cultured in DMEM medium + Glutamax (GIBCO®), supplemented with 10% (v/v) FBS (Invitrogen), at 37°C in a 5% C0 2 humidified atmosphere. Cell identity was confirmed by karyotyping.
- Cytotoxicity Assay The cytotoxic activity of GGG-Val-Cit-PAB-MMAE and the scFv-MMAE conjugates were assessed in a cytotoxicity assay in the presence of cathepsin B. To induce cathepsin B cleavage, MMAE, GGG-Val-Cit-PAB-MMAE or scFv-MMAE conjugate was incubated with 0.01 units of pre- activated cathepsin B (Sigma Aldrich) for 4 hours at 37°C in 25 mM Acetate Buffer pH 4.8. MDA-MB-231 cells were seeded on a 96 well plate at 6000 cells/well overnight.
- the platelet-scFv-MMAE mixture was centrifuged at 2000 g for 2 minutes, the supernatant was removed, and platelets were resuspended in PBS.
- unwashed platelet-scFv-MMAE mixture was used. Either washed or unwashed (control) platelet-scFv-MMAE mixture was added to MDA-MB-231, HT29, HT1080 and PC3 cells in the absence of exogenous cathepsin B and incubated for 72 hours before determination of XTT metabolism as described above.
- Tumor sections were stained overnight with an anti-cathepsin B antibody (Abeam) and detected with an Alexa Fluor 488 labeled anti-mouse antibody (Life Technologies) and cell surface membrane-reactive anti-sodium/potassium ATPase antibody (Abeam), counterstained with Hoechst® (Thermo Fisher Scientific) and visualized using the Nikon Alr Plus Confocal Microscope, 20x water objective.
- Abeam anti-cathepsin B antibody
- Abeam Alexa Fluor 488 labeled anti-mouse antibody
- Abeam cell surface membrane-reactive anti-sodium/potassium ATPase antibody
- Metastasis development was monitored via bioluminescence using IVIS Lumina II by measuring luciferase activity in the chest region, distant from the primary tumor, for a longer time point (60 sec) as previously described Le CP et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nature Communications. 2016; 7: 10634. Metastasis development was quantified using the Living Image software v4.5.1 (Perkin Elmer, Waltham, MA, United States) by quantifying photon/s in a region of interest around the chest bioluminescence signal.
- mice underwent bioluminescence imaging on day 3 and day 7 post tumor inoculation to confirm tumor growth. Mice with tumors were then randomly assigned to three groups and treated with either scFvGPn b/ nia-M AE, scFv mut -MMAE or left untreated. Treatment was initiated 7 days following tumor inoculation, via intravenous injection of 6 mg/kg body weight of either scFv Gpiib/ m a - MMAE or scFv mut -MMAE followed by three additional treatments every fourth day. Primary tumor size and metastasis development was monitored twice a week as described above.
- Tumor samples were fixed in formalin (Sigma Aldrich, St Louis, MO, United States) for 24 hours, paraffin embedded, and microtome sectioned (Leica, Wetzlar, Germany) to 20 pm onto a glass slide. Sections were deparaffinized, stained with Hoechst® and visualized using the Alr Plus Confocal Microscope using a 60x oil objective.
- Mouse blood collection and toxicity measurements Mouse blood was collected via submandibular bleeds into EDTA-coated microtainer collection tubes (BD Biosciences, Franklin Lakes, NJ, United States) and blood counts were performed using the XS- 1000 ⁇ hematologic analyzer (Sysmex Corporation, Kobe, Hyogo, Japan) to determine white blood cells (WBC) and platelets counts. For liver and kidney function tests, 500 pL of mouse blood was collected in citrate.
- ALP alkaline phosphatase
- ALT alanine aminotransferase
- urea levels were measured using the Synchron LX20PRO System (Beckman Coulter Diagnostics, High Wycombe, United Kingdom) by Monash Pathology.
- ADC antibody-drug conjugate
- ADP adenosine diphosphate
- AF Alexa Fluor
- ALP alkaline phosphatase
- ALT alanine aminotransferase
- BLI Bioluminescence
- Cy7 Cyanine 7
- GPIIb/IIIa Glycoprotein Ilb/IIIa
- IC50 half maximal inhibitory concentration
- IVIS In vivo imaging system
- MMAE monomethyl auristatin E
- Mut Mutant
- NHS N-hydroxysuccinimide
- SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis
- scFv single-chain antibodies
- Val-Cit Valine-citrulline
- HRP horseradish peroxidase
- WBC white blood cells
- XTT tetrazolium salt.
- a novel antibody-drug-conjugate was developed.
- the unique scFv GPiib/iiia was employed which specifically targets activated platelets, combined with a sortase A based site-directed biological conjugation method to produce a novel ADC, scFv GPiib/iiia -MMAE incorporating the highly potent anti-mitotic agent (MMAE).
- a MMAE linker was designed with a triglycine (GGG) sequence, a cathepsin B cleavable peptide (Val-Cit) and a para-aminobenzylalcohol (PABA) self-immolative spacer ( Figure 1).
- GGG triglycine
- Val-Cit cathepsin B cleavable peptide
- PABA para-aminobenzylalcohol
- the scFv-MMAE was labeled with a Cy7 dye by NHS labeling to yield, scFv GPiib/ ni a -Cy7-MMAE ( Figure 1).
- SDS page electrophoresis and visualized using the Odyssey reader confirms successful Cy7 labeling of the scFv which has a molecular weight of 34 kDa ( Figure 2A).
- the scFv GPiib/iiia carries a hexahistidine tag downstream of the LPETG sequence, which is cleaved following sortase A reaction, resulting in a final scFv GPiib/ ni a -Cy7- MMAE product with reduced molecular weight compared to the uncleaved scFv GPiib/iiia .
- MMAE conjugation to the scFv was analyzed via Western blotting using an anti-MMAE antibody, confirmed by the presence of a band at 34 kDa ( Figure 2B).
- cytotoxic activity of MMAE on tumor cells was assessed in culture after release from the conjugate by cathepsin B, and the results confirmed equal dose- dependent killing of the triple-negative breast adenocarcinoma cell line MDA-MB- 231 by scFvopii b/iiia -MMAE and scFv mut- MMAE.
- the IC 50 of scFv GPiib/ ni a- MMAE was l.98xlO 10 M while the IC 50 of the scFv mut- MMAE was l.78xlO 10 M ( Figure 3A).
- cathepsin B cleavable linker enables the activation of an inactive prodrug to an active cytotoxic form by utilizing the abundance of cathepsin B in the tumor microenvironment.
- Schmid et al Bioconjug. Chem. 2007:18(3):702-716 disclose the activity of cathepsin B over expressed in solid tumors to cleave a prodrug.
- the IC50 killing efficacy of GGG-Val-Cit-PAB-MMAE on MDA-MB-231 was l.86xl0 8 M and the addition of cathepsin B increased the cellular killing efficacy by approximately 40-fold to 4.70xl0 10 M ( Figure 3B), which is similar to the IC50 of the unmodified MMAE.
- the IC50 killing efficacy of scFv GPiib/ ni a -MMAE was 2.2lxl0 8 M and the addition of cathepsin B enhanced the killing efficacy to l.96xlO 10 M ( Figure 3B).
- MDA-MB-231 cells were incubated with washed human platelets and stained with a CD41 (GPIIb)-specific, non-activation- dependent antibody and two antibodies that are specific for activated GPIIb/IIIa on activated platelets; scFv GPiib/iiia- GFP and PAC-l, the latter antibody binds selectively to activated human GPIIb/IIIa and thus provides a positive control for our scFv GPiib/iiia .
- GPIIb CD41
- MDA-MB-231 cells were found to bind to and directly activated platelets, as shown by increased scFv GPiib/iiia- GFP ( Figure 4A) and PAC-l binding ( Figure 4B). Furthermore, for in vivo characterization, the scFv GPiib/iiia -MMAE was conjugated to Cy7 and the construct injected intravenously to MDA-MB-231 metastatic tumor-bearing mice. Bioluminescence imaging was used to detect areas of primary tumor as shown in Figure 5 A.
- MDA-MB-231, HT29, HT1080 and PC3 cells were incubated with washed human platelets and stained with anti-CD4l antibody as a platelet marker and scFv GPiib/iiia, as a platelet activation marker.
- Bioluminescence imaging of lung and lymph node metastasis was performed by covering the area of the primary tumor site and imaging with a longer exposure time (60 sec) as shown in Figure 5B. Fluorescence imaging of mice was performed 24 hours post injection of scFv GPiib/ ni a -Cy7-MMAE and this demonstrated the enrichment of scFv GPiib/ ni a -Cy7-MMAE at the primary tumor region as well as some nonspecific uptake by the liver (Figure 5C). Following imaging, mice were killed, organs perfused to remove circulating blood and reimaged.
- Example 5 scFvGPiib/nia-Cy7-MMAE localizes to activated platelets in the tumor microenvironment and sites of metastasis but not to resting platelets in the spleen and bone marrow
- MDA-MB-231 tumor-bearing mice were injected with scFv GPiib/ ni a -GFP or scFv mut -GFP and a Dylight 649 anti-GPl b antibody.
- This in vivo approach for immunofluorescence was used as the activated form of GPIIb/IIIa undergoes a conformational change and antigen masking upon tissue fixation and is not recognized by the scFv GPiib/ ni a.
- Example 6 Treatment with scFvGPiib / nia-Cy7-MMAE reduces tumor growth and metastasis
- mice were imaged for bioluminescence signal at day 3 post MDA-MB-231 inoculation, and again at day 7 to confirm the presence of growing tumors (data not shown).
- mice were treated with scFv GPiib/ ni a -MMAE or scFv mut -MMAE and the effect of therapy on tumor growth and metastasis formation was assessed.
- the specification discloses the targeting of activated platelets within the tumor microenvironment as novel strategy for the treatment of cancers including primary tumors and metastatic disease.
- This approach is based on the development of a unique ADC, which targets tumor-associated platelets in the tumor microenvironment using the activated GPIIb/IIIa as an epitope to deliver a therapeutic agent such as a highly potent synthetic anti-mitotic agent.
- a therapeutic agent such as a highly potent synthetic anti-mitotic agent.
- this novel approach allows the specific targeting and release of MMAE, via tumor-derived cathepsin B, whilst sparing untoward systemic side effects.
- ADC efficacy of ADC is highly contingent upon the presence and abundance of the antibody target within the tumor, representing a major limitation for the use of ADCs in several cancer types, which do not express a clinically validated specific antigenic molecular target.
- a particular advantage of the present approach is the possible ubiquitous nature of activated platelets in a broad range of human tumors, including breast (Lal et al., Breast Cancer Research. 20l3;l5:207), colorectal (Li et al., Scientific Reports. 20l7;7(l): 10261), lung (Ji et al., Platelets. 20l5;26(2): 138-142), ovarian (Stone et al., N Engl J Med.
- the inventors initially established the ability of activated platelet-specific scFv for tumor imaging (Yap et al., Theranostics. 20l7;7(l0):2565-2574), thus providing a theranostic approach, allowing for the molecular imaging of tumors as a means to detect tumor-associated platelets and therefore predict those likely to respond to platelet-targeting therapy and treatment of patients with the same antibody conjugated to a cytotoxic agent
- the Examples demonstrate the ability to target the activated platelet as a novel approach to deliver a pro-drug for killing of tumor cells.
- the Valine-citrulline (Val-Cit) linker is used as a cathepsin B cleavable linker requiring the presence of cathepsin B for cleavage and release of free MMAE, the active anti-cancer agent.
- Therapeutic approaches using ADCs, such as MMAE are commonly used to target antigens on the cancer cell surface followed by internalization.
- Activation of the prodrug in the tumor microvasculature might not have taken place (due to lack of Cathepsin B access to the microvasculature) or the active drug might have been flushed from the tumor vessels without any therapeutic effect.
- the inventors proposed that the drug would achieve a high enough local concentration to inhibit tumour growth and surprisingly this is what they found raising the prospect that sufficiently abundent activated platelets are found within the tumour microenvironment for effective delivery of drug to tumor and validating the novel and inventive concept of platelet targeting for the treatment of solid tumors and also for reducing metastases.
- activated platelets Prior to the present disclosure, it was not expected that activated platelets would be abundant in the stroma. Similarly Cathepsin B is not expected to be within the microvasculature.
- an scFv is used as an antibody format, and it offers several advantages.
- the small size allows quick and efficient penetration of the tumor environment.
- the recombinant nature of design offers flexibility with respect to conjugation with drugs to generate a homogenous ADC, as described using a sortase A conjugation method.
- scFvs can be produced in various expression systems, adaptable to clinically applicable purity and scale.
- Our specific scFv GPiib/iiia also possesses two additional advantages for future work aiming for clinical translation: Firstly, the scFv GPiib/ ni a was developed from a human scFv library, reducing the risk of antigenicity. Secondly, scFv GPiib/ ni a is cross reactive between activated platelets from mice and humans (Schwarz et al., Circulation Research. 2006;99(l):25-33).
- composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter.
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Un conjugué médicament-protéine de liaison pour administrer un médicament thérapeutique à un tissu cible tel qu'une tumeur comprend (i) une protéine de liaison comprenant un domaine variable d'anticorps qui se lie spécifiquement à la forme activée de GPIIb/IIIa spécifique des plaquettes conjuguée à (ii) un médicament thérapeutique, la protéine de liaison 5 concentrant le médicament thérapeutique dans le tissu et fournissant une administration ciblée du médicament thérapeutique au tissu. Des compositions comprenant le conjugué sont utilisées dans le traitement de tumeurs. Les méthodes théranostiques utilisent l'administration de la protéine de liaison conjuguée à un agent d'imagerie pour diagnostiquer une tumeur et de la protéine de liaison conjuguée à un agent thérapeutique pour effectuer un traitement.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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AU2018902247A AU2018902247A0 (en) | 2018-06-22 | Therapeutic agent | |
AU2018902247 | 2018-06-22 |
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WO2019241847A1 true WO2019241847A1 (fr) | 2019-12-26 |
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PCT/AU2019/050638 WO2019241847A1 (fr) | 2018-06-22 | 2019-06-21 | Conjugué thérapeutique médicament-protéine de liaison à gpiib/iiia et son utilisation |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005091805A2 (fr) * | 2004-02-13 | 2005-10-06 | The Scripps Research Institute | Procedes et compositions d'inhibition de metastase |
US20090180960A1 (en) * | 2007-12-21 | 2009-07-16 | Baker Medical Research Institute | Diagnosis and treatment of diseases involving platelet activation |
WO2012006633A1 (fr) * | 2010-07-09 | 2012-01-12 | Biogen Idec Hemophilia Inc. | Facteurs de coagulation chimériques |
WO2015070014A1 (fr) * | 2013-11-08 | 2015-05-14 | Biogen Idec Ma Inc. | Composé de fusion procoagulant |
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2019
- 2019-06-21 WO PCT/AU2019/050638 patent/WO2019241847A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005091805A2 (fr) * | 2004-02-13 | 2005-10-06 | The Scripps Research Institute | Procedes et compositions d'inhibition de metastase |
US20090180960A1 (en) * | 2007-12-21 | 2009-07-16 | Baker Medical Research Institute | Diagnosis and treatment of diseases involving platelet activation |
WO2012006633A1 (fr) * | 2010-07-09 | 2012-01-12 | Biogen Idec Hemophilia Inc. | Facteurs de coagulation chimériques |
WO2015070014A1 (fr) * | 2013-11-08 | 2015-05-14 | Biogen Idec Ma Inc. | Composé de fusion procoagulant |
Non-Patent Citations (5)
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